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1.
The thermo transient receptor potential (TRP) ion channels, a recently discovered family of ion channels activated by temperature, are expressed in primary sensory nerve terminals, where they provide information regarding thermal changes in the environment. Six thermo-TRPs have been characterized to date: TRPV1-4, which respond to different levels of warmth and heat, and TRPM8 and TRPA1, which respond to cool temperatures. We review the current state of knowledge of thermo-TRPs, and of the modulation of their thermal thresholds by a range of inflammatory mediators. Blockers of these channels are likely to have therapeutic uses as novel analgesics but may also cause unacceptable side effects. Controlling the modulation of thermo-TRPs by inflammatory mediators may be a useful alternative strategy in developing novel analgesics. 相似文献
2.
The thermo-transient receptor potentials (TRPs), a recently discovered family of ion channels activated by temperature, are expressed in primary sensory nerve terminals where they provide information about thermal changes in the environment. Six thermo-TRPs have been characterised to date: TRP vanilloid (TRPV) 1 and 2 are activated by painful levels of heat, TRPV3 and 4 respond to non-painful warmth, TRP melastatin 8 is activated by non-painful cool temperatures, while TRP ankyrin (TRPA) 1 is activated by painful cold. The thermal thresholds of many thermo-TRPs are known to be modulated by extracellular mediators, released by tissue damage or inflammation, such as bradykinin, PG and growth factors. There have been intensive efforts recently to develop antagonists of thermo-TRP channels, particularly of the noxious thermal sensors TRPV1 and TRPA1. Blockers of these channels are likely to have therapeutic uses as novel analgesics, but may also cause unacceptable side effects. Controlling the modulation of thermo-TRPs by inflammatory mediators may be a useful alternative strategy in developing novel analgesics. 相似文献
3.
The transient receptor potential vanilloid 1 receptor (TRPV1) plays an important role in inflammatory heat hyperalgesia. TRPV1 is a non-selective cation channel gated by noxious heat, protons and capsaicin, thus being regarded as a polymodal molecular integrator in nociception. Abundant evidence has demonstrated that TRPV1 is also modulated by numerous inflammatory mediators, including growth factors, neurotransmitters, peptides or small proteins, lipids, chemokines and cytokines. By activating multiple protein kinases to increase the phosphorylation of TRPV1, pronociceptive inflammatory mediators sensitise the TRPV1 response to noxious heat, protons and capsaicin, thus augmenting thermal hyperalgesia. In contrast, by inhibiting protein kinases or other mechanisms, antinociceptive inflammatory mediators suppress the response of TRPV1 to these stimuli, thus damping thermal hyperalgesia. The positive modulation of TRPV1 by inflammatory mediators may constitute a novel mechanism underlying sustained inflammatory or neuropathic pain. Blocking pronociceptive inflammatory mediator-exerted sensitising effects or boosting antinociceptive inflammatory mediator-induced suppressing effects on TRPV1 should be considered as sources of novel potential therapies to more effectively treat chronic pain conditions. 相似文献
4.
Mast cells are tissue-resident immune effector cells. They respond to diverse stimuli by releasing potent biological mediators into the surrounding tissue, and initiating inflammatory responses that promote wound healing and infection clearance. In addition to stimulation via immunological routes, mast cells also respond to polybasic secretagogues and physical stimuli. Each mechanism for mast cell activation relies on the influx of calcium through specific ion channels in the plasma membrane. Recent reports suggest that several calcium-permeant cation channels of the TRPV family are expressed in mast cells. TRPV channels are a family of sensors that receive and react to chemical messengers and physical environmental cues, including thermal, osmotic, and mechanical stimuli. The central premise of this review is that TRPVs transduce physiological and pathophysiological cues that are functionally coupled to calcium signaling and mediator release in mast cells. Inappropriate mast cell activation is at the core of numerous inflammatory pathologies, rendering the mast cell TRPV channels potentially important therapeutic targets. 相似文献
5.
《Expert opinion on therapeutic targets》2013,17(1):69-81
Background: The transient receptor potential (TRP) superfamily of ion channels are a large and diverse group that have received increased attention in recent years. The sub-family of thermo-TRPs which are regulated by temperature, among other physical and chemical stimuli, are of particular interest for the development of potential pain therapeutics. Objective/methods: We review the advances in the field in recent years, focusing on a rationale for pain therapy and potential challenges associated with these targets. Results/conclusions: Vanilloid-type TRP 1 (TRPV1) is the most well studied and advanced member of the family, with selective agonists and antagonists already in clinical use or development, respectively. Among other thermo-TRPs (including TRPV2 – 4, Ankyrin type TRP 1 (TRPA1) and melastatin type TRP 8 (TRPM8)), TRPA1 and TRPM8 are emerging as promising novel pain targets. 相似文献
6.
Pain is a prevalent biopsychosocial condition that poses a significant challenge to healthcare providers, contributes substantially to a disability, and is a major economic burden worldwide. An overreliance on opioid analgesics, which primarily target the μ-opioid receptor, has caused devastating morbidity and mortality in the form of misuse and overdose-related death. Thus, novel analgesic medications are needed that can effectively treat pain and provide an alternative to opioids. A variety of cellular ion channels contribute to nociception, the response of the sensory nervous system to a noxious stimulus that commonly leads to pain. Ion channels involved in nociception may provide a suitable target for pharmacologic modulation to achieve pain relief. This narrative review summarizes the evidence for two ion channels that merit consideration as targets for non-opioid pain medications: ryanodine receptors (RyRs), which are intracellular calcium channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which belong to the superfamily of voltage-gated K+ channels. The role of these channels in nociception and neuropathic pain is discussed and suitability as targets for novel analgesics and antihyperalgesics is considered. 相似文献
7.
Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B(1) (BDKRB1) and 5-HT(1A) (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information. 相似文献
8.
Ion channels form a diverse and sophisticated collection of membrane-bound proteins. They are influenced by many endogenous compounds and physiological stimuli and modulate neuronal activity. It is thus not surprising that they provide attractive targets for the design of novel therapeutics. In this article, recent ion channel research and its relevance to modulation of sensory transmission is assessed. In pain research, specific blockade or activation of ion channels has long been considered a desired route for identification of analgesics. Historically, this has proven difficult to attain due to the incidence of side-effects associated with most ion-channel modulators. The recent discovery of several novel classes of ion channels, each of which has a specific distribution and role in sensory processing and nociception, has provided a plethora of targets for pharmaceutical intervention with the promise of an improved therapeutic index. 相似文献
9.
Growing evidence implicates an increasing number of novel lipids, including eicosanoids, diacylglycerols, lysophosphatidic acids and ceramides, in augmenting the sensitivity of sensory neurons and enhancing pain perception. Many of these lipids are second messengers in signaling pathways that are associated with increasing the sensitivity of sensory neurons, whereas others are putative inflammatory mediators that activate either surface receptors or ion channels in these neurons. Based on the studies we review, it is clear that lipid-derived inflammatory mediators are a novel group of targets for therapeutics to treat inflammation and chronic pain states. However, much work remains to define the roles of these lipids in inflammation and the cellular mechanisms by which they alter the sensitivity of sensory neurons. 相似文献
10.
The emerging role of TRP channels in mechanisms of temperature and pain sensation 总被引:1,自引:0,他引:1
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Story GM 《Current Neuropharmacology》2006,4(3):183-196
Pain is universal and vital to survival. It is an essential component of our sense of touch; together, touch and pain have evolved to enable our awareness of the intricacies of our environment and to warn us of danger and possible injury. There is a clear link between temperature sensation and pain-painful temperature sensations occur acutely and are a hallmark of inflammatory and chronic pain disorders of the nervous system. Mounting evidence suggests a subset of Transient Receptor Potential (TRP) ion channels activated by temperature (thermoTRPs) are important molecular players in acute, inflammatory and chronic pain states. Varying degrees of heat activate four of these channels (TRPV1-4), while cooling temperatures ranging from pleasant to painful activate two distantly related thermoTRP channels (TRPM8 and TRPA1). ThermoTRP channels are also chemosensitive, being activated and or modulated by plant-derived small molecules and endogenous inflammatory mediators. All thermoTRPs are expressed in tissues essential to cutaneous thermal and pain sensation. This review examines the contribution of thermoTRP channels to our understanding of temperature and pain transduction at the molecular level. 相似文献
11.
Daisuke Kozai Reiko Sakaguchi Tomohiko Ohwada Yasuo Mori 《Current Neuropharmacology》2015,13(2):266-278
The transient receptor potential (TRP) proteins are a family of ion channels that act as
cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators.
Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate
neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an
attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act
on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative
modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic
modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of
TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound
activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with
significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred
through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic
moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and
discuss their modulatory mechanisms. 相似文献
12.
Acute nociceptive pain is caused by the direct action of a noxious stimulus on pain-sensitive nerve endings, whereas inflammatory pain (both acute and chronic) arises from the actions of a wide range of inflammatory mediators released following tissue injury. Neuropathic pain, which is triggered by nerve damage, is often considered to be very different in its origins, and is particularly difficult to treat effectively. Here we review recent evidence showing that members of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channel family - better known for their role in the pacemaker potential of the heart - play important roles in both inflammatory and neuropathic pain. Deletion of the HCN2 isoform from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, but acute pain sensation is unaffected. This work shows that inflammatory and neuropathic pain have much in common, and suggests that selective blockers of HCN2 may have value as analgesics in the treatment of pain. 相似文献
13.
《Expert opinion on drug discovery》2013,8(8):885-900
Introduction: Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G-protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy.Areas covered: This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics.Expert opinion: Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression). 相似文献
14.
Mark Connor Chris W Vaughan Robert J Vandenberg 《British journal of pharmacology》2010,160(8):1857-1871
The myriad functions of lipids as signalling molecules is one of the most interesting fields in contemporary pharmacology, with a host of compounds recognized as mediators of communication within and between cells. The N-acyl conjugates of amino acids and neurotransmitters (NAANs) have recently come to prominence because of their potential roles in the nervous system, vasculature and the immune system. NAAN are compounds such as glycine, GABA or dopamine conjugated with long chain fatty acids. More than 70 endogenous NAAN have been reported although their physiological role remains uncertain, with various NAAN interacting with a low affinity at G protein coupled receptors (GPCR) and ion channels. Regardless of their potential physiological function, NAAN are of great interest to pharmacologists because of their potential as flexible tools to probe new sites on GPCRs, transporters and ion channels. NAANs are amphipathic molecules, with a wide variety of potential fatty acid and headgroup moieties, a combination which provides a rich source of potential ligands engaging novel binding sites and mechanisms for modulation of membrane proteins such as GPCRs, ion channels and transporters. The unique actions of subsets of NAAN on voltage-gated calcium channels and glycine transporters indicate that the wide variety of NAAN may provide a readily exploitable resource for defining new pharmacological targets. Investigation of the physiological roles and pharmacological potential of these simple lipid conjugates is in its infancy, and we believe that there is much to be learnt from their careful study. 相似文献
15.
瞬时感受器电位香草酸受体1(transient receptor potential vanilloid 1,TRPV1)是一种非选择性阳离子通道,主要表达于感觉神经元,可被辣椒素、热刺激、质子等激活。瞬时感受器电位香草酸受体1与疼痛紧密相关,在炎性疼痛、神经病理性疼痛、癌痛等疼痛中发挥着重要作用,是新型镇痛药开发中一个有前景的分子靶点。近年来,研究发现不同化学类型的天然产物对瞬时感受器电位香草酸受体1通道具有调节作用。本文就天然产物通过调节瞬时感受器电位香草酸受体1发挥镇痛作用进行综述。 相似文献
16.
An elevated platelet count is well recognized as a marker of inflammatory bowel disease activity. There is an increased incidence of systemic thromboembolism in this disease. Recent work indicates that platelets exhibit several proinflammatory properties including release of inflammatory mediators, and recruitment, chemotaxis and modulation of the activity of other inflammatory cells. Furthermore there is evidence that microvascular thrombosis and a procoagulant state may play a role in the pathogenesis of inflammatory bowel disease.
These observations prompted recent studies of platelet activity in inflammatory bowel disease, which indicate enhanced platelet aggregation in vivo and in vitro, and increased platelet activation as measured by increased release of intracellular proteins into plasma and expression of platelet surface markers, including P-selectin and GP53. These abnormalities could contribute to the pathogenesis of inflammatory bowel disease by enhancing inflammation and promoting microinfarction. Aminosalicylates reduce platelet activity although they also have many other additional properties to explain their efficacy in inflammatory bowel disease. There are however several specific anti-platelet drugs now available which may provide new therapeutic possibilities in the management of this disease. 相似文献
These observations prompted recent studies of platelet activity in inflammatory bowel disease, which indicate enhanced platelet aggregation in vivo and in vitro, and increased platelet activation as measured by increased release of intracellular proteins into plasma and expression of platelet surface markers, including P-selectin and GP53. These abnormalities could contribute to the pathogenesis of inflammatory bowel disease by enhancing inflammation and promoting microinfarction. Aminosalicylates reduce platelet activity although they also have many other additional properties to explain their efficacy in inflammatory bowel disease. There are however several specific anti-platelet drugs now available which may provide new therapeutic possibilities in the management of this disease. 相似文献
17.
INTRODUCTION: Neuropathic pain (NeP) is an intractable chronic pain condition which severely deteriorates the quality of life of 6% of the population. Caused by direct physical damage or diseases of the nervous system responsible for pain generation and transmission, NeP is manifested as spontaneous pain, hyperalgesia and allodynia. Its treatment is a challenging and unmet medical need. It is generally accepted that inflammatory mediators over-produced in injured nerves play a crucial role in the initiation and maintenance of NeP. AREAS COVERED: Among numerous inflammatory mediators, cyclooxygenase 2 (COX2) and its end product prostaglandin E2 (PGE2) are persistently up-regulated in infiltrating macrophages and Schwann cells in injured nerves and contribute to the development of NeP. In a NeP rat model and an ex vivo model of sensory ganglion explant culture, injured nerve-derived COX2 and PGE2 facilitate the synthesis of pain mediators including neuropeptides, ion channels, cytokines and neurotrophins in primary sensory neurons. EXPERT OPINION: Stimulating the synthesis of pain mediators in primary sensory neurons is a novel mechanism underlying the contribution of injured nerve-derived COX2 and PGE2 to the genesis of NeP. Targeting COX2/PGE2/EP signaling in injured nerves through local administration could open a novel therapeutic avenue to treat this debilitating disease. 相似文献
18.
Bv8 is a small protein secreted by frog skin. Mammalian homologues of Bv8, the prokineticins PK1 and PK2, and their G-protein coupled receptors PKR1 and PKR2 have been identified and linked to several biological effects. Bv8 elicits a dose-dependent reduction in nociceptive threshold to thermal and mechanical stimuli applied to the skin of tail and paw of rats and mice and increases the sensitivity to nociceptive mediators as capsaicin and prostaglandins. The receptors for Bv8/PKs are present in a fraction of peptidergic population of C-fibre neurons, and in a fraction of A myelinated-fibre neurons. In mouse and rat dorsal root ganglia, PKR-expressing neurons also express TRPV1 and the activation of PKRs sensitises TPRV1 to the action of capsaicin. Mice lacking PKR1 gene exhibit impaired Bv8-induced hyperalgesia, develop deficient responses to noxious heat, capsaicin and protons and show reduced thermal and mechanical hypersensitivity to paw inflammation, indicating a requirement for PKR1 signalling associated with activation and sensitisation of primary afferent fibres. PKs are highly expressed by neutrophils and other inflammatory cells and must be considered as new pronociceptive mediators in inflammatory tissues. Bv8-like hyperalgesic activity was demonstrated in extracts of rat inflammatory granulocytes. Bv8 stimulate macrophage and T lymphocyte to differentiate between an inflammatory and Th1 profile indicating that Bv8/PK proteins play a role in immuno-inflammatory responses. Blockade of PKRs may represent a novel therapeutic strategy in acute and inflammatory pain conditions. 相似文献
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20.
Noxious thermal, mechanical, or chemical stimuli evoke pain through excitation of the peripheral terminals called nociceptor, and many kinds of ionotropic and metabotropic receptors are involved in this process. Capsaicin receptor TRPV1 is a nociceptor-specific ion channel that serves as the molecular target of capsaicin. TRPV1 can be activated not only by capsaicin but also by noxious heat (with a thermal threshold >43 degrees C) or protons (acidification), all of which are known to cause pain in vivo. Studies using TRPV1-deficient mice have shown that TRPV1 is essential for selective modalities of pain sensation and for thermal hyperalgesia. One mechanism underlying inflammatory pain which is initiated by tissue damage/inflammation and characterized by hypersensitivity is sensitization of TRPV1. In addition to TRPV1, there are five thermosensitive ion channels in mammals, all of which belong to the TRP (transient receptor potential) super family. These include TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. These channels exhibit distinct thermal activation thresholds (> 52 degrees C for TRPV2, > approximately 34-38 degrees C for TRPV3, > approximately 27-35 degrees C for TRPV4, < approximately 25-28 degrees C for TRPM8 and < 17 degrees C for TRPA1) and are expressed in primary sensory neurons as well as other tissues. Some of the thermosensitive TRP channels are likely to be involved in thermal nociception, since their activation thresholds are within the noxious range of temperatures. 相似文献